Methods of inhibiting adverse cardiac events and treating atherosclerosis and coronary artery disease using galectin-3 binding protein (gal-3bp, btbd17b, mac-2 binding protein)

Abstract

The invention provides Galectin-3 binding protein (Gal-3BP, BTBD17B) polypeptide sequences and compositions that include Gal-3BP polypeptide sequences, and methods of using Gal-3BP polypeptide sequences, including modified forms and wild type (native) forms of Gal-3BP polypeptide, such as in treatment, diagnostic, detection and prognostic methods.

1 . A method of reducing or decreasing risk of an adverse cardiovascular event or cardiovascular disease in a subject, comprising administering a Galectin-3 binding protein (Gal-3BP) polypeptide to a subject in an amount that increases Gal-3BP polypeptide in the subject thereby reducing or decreasing risk of the adverse cardiovascular event or cardiovascular disease in the subject. 
     
     
         2 . The method of  claim 1 , wherein the cardiovascular disease is coronary artery disease, peripheral artery disease, cerebrovascular disease, or renal artery disease. 
     
     
         3 . The method of  claim 1 , wherein the adverse cardiovascular event comprises a stroke, myocardial infarction (heart attack), ischemic heart failure, transient ischemic attack or brain trauma. 
     
     
         4 . A method of reducing, inhibiting, or decreasing risk of artherosclerotic plaque formation in a subject, comprising administering a Galectin-3 binding protein (Gal-3BP) polypeptide to a subject in an amount that increases Gal-3BP polypeptide in the subject thereby reducing, inhibiting, or decreasing risk of artherosclerotic plaque formation in the subject. 
     
     
         5 . (canceled) 
     
     
         6 . The method of any of  claims 1  or  4 , wherein the Gal-3BP polypeptide increases to an amount in the subject of greater than 2 ug/ml or 5 ug/ml or 10 ug/ml in blood plasma. 
     
     
         7 .- 10 . (canceled) 
     
     
         11 . The method of any of  claims 1  or  4 , wherein the subject has had or is at risk of an adverse cardiovascular event. 
     
     
         12 . The method of any of  claims 1  or  4 , wherein the subject is at risk of or has an existing cardiovascular disease. 
     
     
         13 . The method of any of  claim 1 ,  4  or  51  or  4 , wherein the Gal-3BP polypeptide comprises a polypeptide fragment of full length Gal-3BP polypeptide. 
     
     
         14 . The method of  claims 1  or  4 , wherein the Gal-3BP polypeptide is mammalian. 
     
     
         15 . The method of  claims 1  or  4 , wherein the Gal-3BP polypeptide is human,  Pan troglodytes, Canis lupus familiaris, Bos Taurus, Mus musculus  or  Rattus norvegicus , SEQ ID NOs:1-6, respectively. 
     
     
         16 . The method of  claims 1  or  4 , wherein the Gal-3BP polypeptide comprises 
       
         
           
                 
                 
               
                           10         20         30         40         50         60 
                     
                 
                   MTPPRLFWVW LLVAGTQGVN DGDMRLADGG ATNQGRVEIF YRGQWGTVCD NLWDLTDASV 
                 
                     
                 
                         70         80         90        100        110        120 
                 
                   VCRALGFENA TQALGRAAFG QGSGPIMLDE VQCTGTEASL ADCKSLGWLK SNCRHERDAG 
                 
                     
                 
                          130        140        150        160        170        180 
                 
                   VVCTNETRST HTLDLSRELS EALGQIFDSQ RGCDLSISVN VQGEDALGFC GHTVILTANL 
                 
                     
                 
                          190        200        210        220        230        240 
                 
                   EAQALWKEPG SNVTMSVDAE CVPMVRDLLR YFYSRRIDIT LSSVKCFHKL ASAYGARQLQ 
                 
                     
                 
                          250        260        270        280        290        300 
                 
                   GYCASLFAIL LPQDPSFQMP LDLYAYAVAT GDALLEKLCL QFLAWNFEAL TQAEAWPSVP 
                 
                     
                 
                          310        320        330        340        350        360 
                 
                   TDLLQLLLPR SDLAVPSELA LLKAVDTWSW GERASHEEVE GLVEKIRFPM MLPEELFELQ 
                 
                     
                 
                          370        380        390        400        410        420 
                 
                   FNLSLYWSHE ALFQKKTLQA LEFHTVPFQL LARYKGLNLT EDTYKPRIYT SPTWSAFVTD 
                 
                     
                 
                          430        440        450        460        470        480 
                 
                   SSWSARKSQL VYQSRRGPLV KYSSDYFQAP SDYRYYPYQS FQTPQHPSFL FQDKRVSWSL 
                 
                     
                 
                          490        500        510        520        530        540 
                 
                   VYLPTIQSCW NYGFSCSSDE LPVLGLTKSG GSDRTIAYEN KALMLCEGLF VADVTDFEGW 
                 
                     
                 
                          550        560        570        580 
                 
                   KAAIPSALDT NSSKSTSSFP CPAGHFNGFR TVIRPFYLTN SSGVD 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         17 . The method of  claims 15  or  16 , wherein the Gal-3BP polypeptide fragment is residues 24-124 (SRCR domain); residues 153-221 (BTB domain); or residues 260-360 (BACK domain). 
     
     
         18 . The method of any of  claims 1  or  4 , wherein the Gal-3BP polypeptide comprises a fusion polypeptide, or a chimeric polypeptide. 
     
     
         19 . The method of  claim 18 , wherein the chimeric polypeptide comprises a Gal-3BP/Immunoglobulin fusion polypeptide. 
     
     
         20 .- 29 . (canceled) 
     
     
         30 . The method of any of  claims 1  or  4 , wherein the subject has or is a candidate for a blood cholesterol lowering therapy. 
     
     
         31 .- 40 . (canceled) 
     
     
         41 . A method of reducing or inhibiting foam cell formation in a subject, comprising administering a Galectin-3 binding protein (Gal-3BP) polypeptide to a subject in an amount that increases Gal-3BP polypeptide in the subject thereby inhibiting or reducing foam cell formation in the subject. 
     
     
         42 . (canceled) 
     
     
         43 . An isolated or purified subsequence of full length Galectin-3 binding protein (Gal-3BP) polypeptide, wherein the subsequence reduces or inhibits macrophage cell expression of scavenger receptor A or CD36, reduces or inhibits foam cell formation or reduces or inhibits modified LDL uptake by macrophages. 
     
     
         44 . A pharmaceutical composition comprising Galectin-3 binding protein (Gal-3BP) polypeptide or a subsequence of full length Galectin-3 binding protein (Gal-3BP) polypeptide, wherein the Galectin-3 binding protein (Gal-3BP) polypeptide or subsequence reduces or inhibits macrophage cell expression of scavenger receptor A or CD36, reduces or inhibits foam cell formation or reduces or inhibits modified LDL uptake by macrophages. 
     
     
         45 . The subsequence of Galectin-3 binding protein (Gal-3BP) polypeptide of  claim 43  or  44 , wherein the subsequence consists of BTBD17B residues 24-124 (SRCR domain); residues 153-221 (BTB domain); residues 260-360 (BACK domain), or a subsequence of BTBD17B residues 24-124 (SRCR domain); residues 153-221 (BTB domain); residues 260-360 (BACK domain). 
     
     
         46 . The subsequence of  claims 43  or  44 , wherein the subsequence of Gal-3BP residues 24-124 (SRCR domain); residues 153-221 (BTB domain); or residues 260-360 (BACK domain) is about 5-10, 10-20, 20-50, 50-75 or 50-100 amino acids in length. 
     
     
         47 . The subsequence of Galectin-3 binding protein (Gal-3BP) polypeptide of  claims 43  or  44 , wherein the subsequence comprises a fusion construct. 
     
     
         48 . The subsequence of  claim 47 , wherein the fusion construct comprises a chimeric polypeptide. 
     
     
         49 . The subsequence of Galectin-3 binding protein (Gal-3BP) polypeptide of  claims 49  or  50 , wherein the subsequence is about 5-10, 10-20, 20-50, 50-100, 100-150, 150-200, 200-250, 250-300, 300-350, 350-400, 400-500, 500-600 or more amino acids in length, and less than full length Gal-3BP polypeptide sequence. 
     
     
         50 . A method of diagnosing a subject having or at increased risk of having an adverse cardiovascular event or cardiovascular disease, artherosclerotic plaque formation, foam cells or foam cell formation, comprising contacting a biological material or sample from a subject with an agent that binds to Gal-3BP polypeptide sequence and assaying for the amount of Gal-3BP polypeptide, wherein an amount less than about 10 ug/ml diagnoses the subject as having or at increased risk of developing an adverse cardiovascular event, cardiovascular disease, artherosclerotic plaque formation, foam cells or foam cell formation. 
     
     
         51 . The method of  claim 50 , wherein the agent comprises an antibody that binds to Gal-3BP polypeptide or a nucleic acid that hybridizes to a nucleic acid encoding Gal-3BP polypeptide sequence. 
     
     
         52 . The method of  claim 50 , wherein the cardiovascular disease comprises coronary artery disease, peripheral artery disease, cerebrovascular disease, or renal artery disease. 
     
     
         53 . The method of  claim 50 , wherein the adverse cardiovascular event comprises stroke, myocardial infarction (heart attack), ischemic heart failure, transient ischemic attack or brain trauma. 
     
     
         54 . The method of  claim 50 , wherein the subject is human. 
     
     
         55 . The method of  claim 50 , wherein the sample is blood or plasma.